Journal
DIABETOLOGIA
Volume 51, Issue 2, Pages 298-308Publisher
SPRINGER
DOI: 10.1007/s00125-007-0889-4
Keywords
AKT; Beta cell viability; c-jun N terminal kinase; inflammation; insulin production; Inflammation; islet transplantation; mitogen activated protein kinase; pancreatic islets
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Funding
- NCRR NIH HHS [U42 RR016603, M01RR16587] Funding Source: Medline
- NIDDK NIH HHS [DK-25802-21, DK-59993] Funding Source: Medline
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Aims/hypothesis Activation of c-jun N-terminal kinase (JNK) has been described in islet isolation and engraftment, making JNK a key target in islet transplantation. The objective of this study was to investigate if JNK inhibition with a cell-permeable TAT peptide inhibitor (L-JNKI) protects functional beta cell mass in human islets and affects AKT and its substrates in islet cells. Methods The effect of L-JNKI (10 mu mol/l) on islet count, mitochondrial membrane potential, glucose-stimulated insulin release and phosphorylation of both AKT and its substrates, as well as on reversal of diabetes in immunodeficient diabetic Nu/Nu mice was studied. Results In vitro, L-JNKI reduced the islet loss in culture and protected from cell death caused by acute cytokine exposure. In vivo, treatment of freshly isolated human islets and diabetic Nu/Nu mice recipients of such islets resulted in improved functional beta cell mass. We showed that L-JNKI activates AKT and downregulates glycogen synthase kinase-3 beta (GSK-3B) in human islets exposed to cytokines, while other AKT substrates were unaffected, suggesting that a specific AKT/GSK-3B regulation by L-JNKI may represent one of its mechanisms of cytoprotection. Conclusions/interpretation In conclusion, we have demonstrated that targeting JNK in human pancreatic islets results in improved functional beta cell mass and in the regulation of AKT/GSK3B activity.
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